tbuckley/cabot-search huggingface dataset:
A phase 1, first-in-human (FIH) study of autologous macrophages engineered to express an anti-HER2 chimeric antigen receptor (CAR) in participants (pts) with HER2-overexpressing solid tumors.
Authors: Yara Abdou, Elizabeth Claire Dees, Joanne E. Mortimer, Paula R Pohlmann, Melissa Lynne Johnson, Richard T. Maziarz, Jennifer M. Specht, Yuan Yuan, Naoto T. Ueno, Mathew Angelos, Saar Gill, Amy Ronczka, Thomas Condamine, Daniel Cushing, Debora Barton, Michael Klichinsky, Ramona F. Swaby, Kim Anna Reiss
Journal: Journal of Clinical Oncology (2023)

TPS2666 Background: Macrophages are abundant in the solid tumor microenvironment (sTME) and can promote tumor growth (M2) or enhance anti-tumor immunity (M1). CAR expression can redirect macrophage function to selectively target and phagocytose antigen overexpressing cancer cells. CAR-M can reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and anti-tumor immunity. CT-0508 is comprised of autologous monocyte-derived proinflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies showed that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden, prolonged survival, and was safe. Notably, anti-HER2 CAR-M treatment led to activation of the sTME, with infiltration of CD8+ and CD4+ T cells, NK cells, dendritic cells, and increased activated CD8+ tumor infiltrating lymphocytes. In a pre-clinical anti-PD1 resistant solid tumor model, mice that received anti-HER2 CAR-M and anti-PD1 demonstrated improved tumor control, overall survival, and TME activation compared to single treatment alone, indicating synergy and capacity for CAR-M to sensitize solid tumors to checkpoint blockade. Methods: This Phase 1, First in Human study evaluates the safety, tolerability, cell manufacturing feasibility, trafficking, TME activation, and preliminary evidence of efficacy of investigational product CT-0508 in 18 participants (pts) with locally advanced (unresectable) /metastatic solid tumors overexpressing HER2. Pts previously treated with anti-HER2 therapies are eligible. Filgrastim mobilized autologous CD14+ monocytes are collected by apheresis, followed by manufacturing and cryopreservation. Group 1 pts (n = 9; enrollment complete) received fractionated doses of CT-0508 over Days 1, 3, and 5. Group 2 pts (n = 9) receive CT-0508 as a single infusion on D1. Additional cohorts include: CT-0508 co-administered with pembrolizumab and CT-0508 monotherapy administered intraperitoneally in pts with peritoneal predominant disease. Correlative assessments include pre- and post-treatment biopsies and blood samples for safety (immunogenicity), trafficking (PCR, RNA scope), CT-0508 persistence in blood and tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others. Clinical trial information: NCT04660929 .
Tracking plasticity along with proliferation and immune evasion using FOXC1, MKI67 and PDL1 for prediction of therapeutic response and risk for hyperprogressive disease with PD1/PDL1 inhibitors in advanced/metastatic cancers: Pan-tumor validation in clinical trial and real-world cohorts.
Authors: Partha S Ray, Tania Ray, Clive R Taylor, Robert Hussa
Journal: Journal of Clinical Oncology (2023)

2627 Background: Accurate prediction of therapeutic response (TR) to treatment with immune checkpoint blockade (ICB) as well as any resultant durable clinical benefit in terms of improved progression-free survival (PFS) and overall survival (OS) is not consistently achieved with existing biomarkers like PDL1 or tumor mutational burden (TMB). We hypothesized that a multi-marker predictive biomarker strategy that tracks plasticity using FOXC1 expression, in parallel to tumor proliferation and immune evasion, using expression of MKI67 and PDL1, respectively, may demonstrate superior TR prediction, and also enable accurate prediction of risk for hyperprogressive disease (HPD). Methods: Pre-treatment tumor RNA-Seq data obtained from training/validation clinical trial cohorts and real-world patients diagnosed with advanced/metastatic non-small cell lung cancer (NSCLC, n=82/28) and melanoma (n=154/121) were analyzed for FOXC1, MKI67 and PDL1 expression, and correlated with overall response rate (ORR), PFS, OS and HPD, the latter defined as time-to-treatment-failure &lt;=2 months post-treatment initiation. Optimized biomarker cutoff values based on model area-under-curve were leave-one-out cross validated and cancer-type specific (CTS) prediction algorithms derived. The unmodified strategy was then validated in the independent, CTS validation datasets. Results: ORR prediction accuracy was confirmed in validation datasets with high accuracy: NSCLC AUC=0.96, OR=9.63 (0.98-94.54, 95%CI) p=0.03 and melanoma AUC=0.91, OR=3.85 (1.73-8.58, 95%CI), p=0.0005. Predicted Responders consistently displayed superior PFS and OS compared to predicted Non-Responders: NSCLC PFS HR=0.51 (0.32-0.82, 95%CI) p=0.007, OS HR=0.44 (0.27-0.73, 95%CI) p=0.003; melanoma PFS HR=0.45 (0.30-0.68, 95%CI) p=0.002, OS HR=0.43 (0.26-0.71, 95%CI) p=0.002. Patients at risk for HPD were identified with high accuracy: NSCLC AUC=0.96, OR=9.67 (2.95-31.73) p&lt;0.0001; melanoma AUC=0.98, OR=44.36 (11.73-167.74, 95%CI) p&lt;0.0001. Conclusions: Tracking multiple dimensions of cancer biology including plasticity (using FOXC1), as opposed to tracking immune evasion alone, proved to be a superior and accurate pan-cancer, tissue-agnostic predictor of TR to ICB therapy in advanced/metastatic tumors in terms of ORR, PFS, OS as well as HPD risk prediction. This approach merits further testing in prospective clinical trials.
Clinical trends of children with primary cardiac tumors: 15-year experience from a single center.
Authors: Nishant Patel, Dan Dong, Peicheng Ding, Kede Wu, Zhaocong Yang, Xuming Mo
Journal: Journal of Clinical Oncology (2023)

e22008 Background: Clinical presentation of pediatric primary cardiac tumors is exceptionally rare throughout the world. The purpose of our study is to evaluate clinical intervention by following up on children with primary cardiac tumors. Methods: Our study retrospectively enrolled 97 children diagnosed with primary cardiac tumors from Jan 2005 to Dec 2020 in a single center, Children’s Hospital of Nanjing Medical University by confirming with clinicoradiological and non-invasive diagnostic procedures. Primary outcome was to measure clinical trends and interventions while secondary was to analyze survival of 26 (26.80%) operative and 71 (73.19%) non-operative patients. Surgical intervention patients were followed for 6 Mo in the first postoperative year, then every year. Meanwhile, non-serious, asymptomatic, and no hemodynamic changes patients were treated non-operatively and followed up every year regularly. Results: In primary outcome, median age of children was 4.72±4.10 years (1d~16y), and median follow-up was 5.60±4.97 years (1m~15y). Most enrolled children were younger than 1 year old at the time of diagnosis. Primary cardiac tumors patients consisting of 60 rhabdomyoma (61.85%), 11 myxomas (11.34%), 7 fibromas (7.21%), 3 lymphangiomas (3.09%), 2 lipomas (2.06%), 9 unclassified tumors (9.27%) and 5 malignant tumors (5.15%) were retrospectively analyzed. Major 75 patients (77.31%) were diagnosed during various treatments of clinical symptoms, whereas 18 (18.55%) were diagnosed with routine investigation and 14 (14.43%) were diagnosed by prenatal fetal echocardiography. Herein, 26 children with critical symptoms and serious hemodynamic alteration had undergone surgical intervention in our hospital. Among them, 6 (23.07%) patients had postoperative complications; 2 (7.7%) patients were unable to survive due to post-operative arrhythmia and low cardiac output syndrome; While 2 (7.7%) patients with myxomas had a reoccurrence, and 2 (7.7%) patients had been diagnosed with another rhabdomyoma after intervention, others recovered well. Meanwhile, 71 children had non-surgical management, where 8 (11.26%) were lost to follow-up; 3 (4.22%) patients with malignant tumors were unable to survive after discharge due to unknown causes, and other patients had no serious symptoms or growth of tumors during follow-up. In secondary outcome, survival between operative and non-operative patients had no significant difference ( P &gt; 0.05). Conclusions: Clinical intervention of pediatric primary cardiac tumors may be performed one-on-one by accounting presentations, symptoms, and emergence even though majority of primary cardiac tumors in children are benign in nature, and postoperative reoccurrence is feasible, particularly for rhabdomyoma. Meanwhile, the primary goal of surgical intervention is to reinstate normal hemodynamics, and preserve significant structures and cardiac tissues.
Real-world (RW) use of venetoclax (VEN) in patients (pts) with acute myeloid leukemia (AML) in a US RWE database (COTA).
Authors: Amer Methqal Zeidan, Leyla Hernandez Donoso, Sejla Hodzic, Henry F Owusu, Dhrubajyoti Pathak, Summera Qiheng Zhou, Eytan Stein
Journal: Journal of Clinical Oncology (2023)

7044 Background: VEN + hypomethylating agents (HMAs)/low-dose cytarabine was approved for the treatment (tx) of pts with AML who are ≥75 y or ineligible for intensive chemotherapy (CT) in 11/2018. To understand the use, safety, and efficacy of VEN in clinical practice, the COTA AML database, using pt-level curated electronic health record data from centers across the US, was analyzed. Methods: This is a retrospective, descriptive analysis of deidentified secondary data from the COTA AML database in the US. Data was abstracted for adults diagnosed with AML who initiated first-line (1L) tx on or after 01/01/2018 and received ≥1 VEN tx at any point. Pts with no diagnosis date or with concurrent primary malignancies were excluded. Follow-up was until the last recorded event (last visit or death). The study period for this analysis was 01/2018 to 09/2022. Results: Of 3836 pts with AML in the database, 1163 pts initiated 1L tx in or after 2018; of these, 636 received ≥1 VEN tx at any point. See Table for baseline demographic data. Most VEN-treated pts were seen by community healthcare providers (407/636, 64%). Genetic/molecular data were limited. Of the most frequently tested mutations, the most common were TP53 (129/461, 28%), RUNX1 (109/444, 25%), TET2 (101/414, 24%), ASLX1 (92/417, 22%), and DNMT3A (91/424, 22%). Of pts who received VEN, 47% (299/636) received 1L VEN, and the majority (269/636, 42%) received VEN + HMAs. For pts with tx prior to VEN (pretreated), 262/337 (78%) were previously treated with CT. 1L pts were more often treated in community centers than pretreated pts (73% vs 56%), had more comorbidities (56% vs 40%), and TP53 positivity (19% vs 10%) at baseline. Of 284 VEN-treated pts with available response data, 180 (63%) had a complete response (CR). Median OS (mOS) of VEN-treated pts was 14.4 mo from 1L tx initiation (de novo AML, 17 mo; secondary AML, 14 mo). mOS from diagnosis was 14 mo for newly diagnosed and 18 mo for pretreated pts. Toxicity was the main cause of dose reduction and discontinuation. Median duration of VEN tx was 78 d. Dose reduction was reported in ~30% of VEN-treated pts. Of VEN-treated pts, 53% (338/636) discontinued at least 1 VEN regimen, with a median time to discontinuation of 49.5 d. Conclusions: This study provides an overview of the RW use of VEN in pts with AML in the US since its approval in 11/2018. Despite the study period starting earlier than VEN approval, almost half of pts with AML who initiated tx after 2018 received 1L VEN. The RW CR rate in VEN-treated pts with available data was 63%, but over half of VEN-treated pts had VEN tx discontinuation. [Table: see text]
Differences in real-world pembrolizumab dosing patterns (every 3 weeks versus every 6 weeks) across a large cancer center network.
Authors: Divya Natesan, Priyanka Vinod Chablani, Hong Wang, Mark Jelinek, Margaret Q. Rosenzweig, Risa Liang Wong
Journal: Journal of Clinical Oncology (2023)

2592 Background: Pembrolizumab (pembro) is an intravenous immune checkpoint inhibitor used for anti-cancer treatment, with equivalent monotherapy dosing options of 200 mg every 3 weeks (Q3W) or 400 mg every 6 weeks (Q6W). Pembro Q6W dosing was approved for use in April 2020 after the Q3W dose had already been established. As pembro dosing patterns in real-world practice are not well-described, we evaluated this in a large cancer center network consisting of a central site (CS) and 36 community network sites (NS). Methods: We retrospectively reviewed the charts of all patients who received pembro monotherapy for cancer treatment between 4/2020 – 4/2022 at UPMC Hillman Cancer Center sites across the state of Pennsylvania, as well as sites in New York and Ohio. We performed statistical comparisons using the Fisher’s exact test and Wilcoxon rank-sum test. Results: We identified 1,640 patients who received pembro monotherapy, including 377 patients at the CS and 1,263 patients in the NS, with characteristics displayed. Pembro Q6W dosing was significantly more common at the CS than in the NS (42% vs. 15%, p&lt;0.0001). When analyzed by tumor type, pembro Q6W dosing was significantly more common at the CS than in the NS for head &amp; neck (53% vs. 11%, p&lt;0.0001), thoracic (49% vs. 15%, p&lt;0.0001), skin (60% vs. 19%, p&lt;0.0001), and genitourinary (30% vs. 16%, p=0.015) cancers, but not for other tumor types. Within the NS, 30% (11/36) of sites only utilized pembro Q3W dosing and never administered Q6W dosing to patients. Of note, some patients who received pembro Q6W dosing received pembro Q3W dosing initially, either as part of a pembro-containing multidrug regimen or as monotherapy. Excluding patients initially treated with a multidrug regimen to reduce confounding factors, we found that of the patients who received pembro Q6W dosing, 47% (65/137) at the CS and 28% (48/169) in the NS were initially treated with pembro Q3W monotherapy before transitioning to Q6W monotherapy (p=0.0008). Conclusions: In our large cancer center network, pembro Q6W dosing was significantly more common at the CS than in the NS. Switching from pembro Q3W to Q6W dosing was also significantly more common at the CS. Further work is needed to clarify the patient, provider, and institutional factors influencing differences in pembro dosing patterns in real-world practice, as well as the impact of dosing patterns on care delivery outcomes such as cost and accessibility. [Table: see text]
First-line treatment of fecal microbiota transplantation for immune-mediated colitis.
Authors: Yinghong Wang, Krishnavathana Varatharajalu, Malek Shatila, Matthew T Campbell, Pavlos Msaouel, Craig A. Kovitz
Journal: Journal of Clinical Oncology (2023)

2510 Background: The management of moderate to severe immune-mediated colitis (IMC) includes immunosuppression with steroids and/or biologic agents. Long-term immunosuppression increases the risk for infections and steroid side-effects. Fecal microbiota transplantation (FMT) is increasingly used for the treatment of refractory IMC but has not been studied in the front-line setting. Here we aim to test the hypothesis that front-line FMT can alleviate IMC symptoms while reducing unnecessary exposure to steroids and their complications. Methods: We will report interim data from a prospective clinical trial exploring the efficacy and safety of FMT as a first-line treatment for IMC. To be included, patients had to 1) have symptoms of immune-mediated diarrhea or colitis grade ≥ 2 within 45 days of FMT and 2) not have received any immunosuppressive treatment for IMC or any other indication around the time of FMT. Results: Seven patients have been enrolled in the trial thus far. Patients received front-line FMT within a median of 35 days (IQR: 18-57 days) from IMC onset. Five (71.4%) patients had symptom improvement within a median of 1 day (IQR: 1-5 days) after FMT. The only FMT-related adverse events reported were transient fever and self-resolving abdominal cramping in three patients (42.8%) within the first week of FMT. All patients stopped immunotherapy due to IMC. Six (85.7%) were able to resume cancer treatment after FMT with 4 patients (57.1%) resuming immunotherapy. Four patients (57.1%) had colitis remission by the end of the study period, with one additional patient showing signs of symptom improvement but passing away before IMC outcome could be assessed. Conclusions: This study is the first to evaluate the safety and efficacy of front-line FMT for the treatment of IMC. While more patients are needed before final conclusions can be drawn, our initial results suggest that FMT can be an effective first-line treatment for IMC that can be delivered in a timely manner and quickly provide symptom relief in a majority of patients while avoiding the use of steroids and allowing the safe resumption of immunotherapy. Therefore, first-line FMT may be a safe and effective steroid sparing alternative to the current standard of care treatment for IMC. Clinical trial information: NCT04038619 . [Table: see text]
Efficacy and safety in unresectable hepatocellular carcinoma using atezolizumab plus bevacizumab in later-line: A retrospective analysis of real-world evidence.
Authors: Jiamin Cheng, Bowen Chen, Xinfeng Zhang, Guodong Su, Caiyun Peng, Lin Zhou, Jin Lei, Yinyin Li, Yinying Lu
Journal: Journal of Clinical Oncology (2023)

e16173 Background: As far, no data has been published about later-line application of atezolizumab plus bevacizumab (T+A) in patients with unresectable hepatocellular carcinoma (uHCC). Methods: We retrospectively recruited uHCC patients who treated with later-line T+A. Efficacy endpoints included overall survival (OS) and progression free survival (PFS), in accordance with RECIST v1.1. Safety was evaluated with CTCAE v5.0. We also continually enrolled uHCC patients who received later-line regorafenib plus PD-1 inhibitors (Reg+PD-1) as a comparison. Results: Total 33 patients were continually included, 12 used T+A and 21 chose Reg+PD-1. Baseline performance status, liver function and BCLC tumor stage were similar between two cohorts. At data cut-off at February 2023, following median following-up at 18.9 months, median OS in cohort T+A and Reg+PD-1 were 8.2 (95%CI: 5.8-10.6) vs 15.6 (95%CI: 7.6-23.6) (p = 0.237). Median PFS in cohort T+A and Reg+PD-1were 5.1 (95%CI: 1.1-9.1) vs 3.5 (95%CI: 2.1-4.9) (p = 0.575). OS rate and PFS rate are listed. None of efficacy endpoints reached statistical difference. All patients suffered from AEs. No AEs-related death occurred. Conclusions: Efficacy and safety of later-line T+A in uHCC patients was similar with those who used regorafenib plus PD-1 inhibitors, which needed to be further confirmed. [Table: see text]
Impact of surgical weight loss treatments on care burden among obese endometrial cancer survivors.
Authors: Katia Noyes, Ajay A Myneni, Joseph Boccardo, Emese Zsiros, Aaron B Hoffman
Journal: Journal of Clinical Oncology (2023)

5607 Background: Among obesity-related cancers globally, 40% of disability adjusted life years lost are attributed to endometrial cancer (EC). EC patients are more likely to die of obesity-related complications rather than the cancer itself. Metabolic and bariatric surgery (MBS) is an effective weight loss treatment that has been shown to reduce prevalence and severity of many obesity-related chronic conditions. However, there is limited evidence on MBS on EC survivors. We examined the burden of patient healthcare utilization among EC survivors who did and did not undergo MBS. Methods: We utilized the SEER-Medicare database to identify 31,437 patients diagnosed with endometrial cancer between 2015 and 2017. We selected 9,229 (29.4%) patients with documented obesity (ICD codes) among whom 75 (0.8%) patients underwent MBS after completing EC treatment (2017-2019). EC survivors with and without a history of MBS were matched on age at EC diagnosis. We examined annualized Medicare inpatient and provider claims payments among EC-MBS (starting 3 months after the surgery, n=66) and EC-no MBS patients (2017-2019) and used Wilcoxon Rank-Sum tests to examine differences in payments in a 1:5 matched sample. Results: EC-MBS patients were younger (59.9 years) at the time of cancer diagnosis compared to EC-no MBS patients (68.2 years, p&lt;0.01). In an age-matched sample, annualized median inpatient and provider claim payments among EC-MBS patients ($1,824) were lower than that of EC-no MBS patients ($2,920, p&lt;0.01). Conclusions: Surgical weight loss achieves rapid and effective weight loss and has the potential to lower healthcare utilization among EC survivors but less than 1% of eligible patients receive the surgery. Further research is needed to better understand patient, provider, and access barriers to surgical weigh loss in patients with obesity-related cancers. [Table: see text]
Using cell-free DNA to predict response to immunotherapy in non-small cell lung cancer pre- and post-treatment.
Authors: Satyanarayan Rao, Alexis Zukowski, Abigail Weirich, Peter Kabos, Elin Marie Stensland, Inger Johanne Zwicky Eide, Odd Terje Brustugun, Srinivas Ramachandran
Journal: Journal of Clinical Oncology (2023)

e21198 Background: Despite revolutionizing cancer therapy, immune checkpoint inhibitors (ICI) still do not benefit a significant proportion of patients. The risks associated with ICI-related adverse events, mixed performance of PD-L1 staining in predicting treatment response and its high cost, present a clinical need for more precise methods to define disease states in the context of ICI treatment. ICI response is thought to depend on the phenotype of the tumor and the associated immune response, especially functional state of CD8+ T cells in the tumor microenvironment (TME). Methods: Here we show that the CD8+ T cell signatures from plasma cell-free DNA (cfDNA) could be used to predict response of patients to anti-PD-1 therapy, using samples collected before and shortly after start of treatment. Blood samples were drawn just before the first dose, 1 day to 1 week before the start of treatment and 45-60 days since start of treatment. The treatment duration varied depending on response. Response was evaluated by CT scans every 8-12 weeks. 11 of the samples are from patients with no or minor response ( &lt; 6 months of treatment), and 12 are from patients with prolonged benefit of the medication ( &gt; 1 year of treatment). Exhausted CD8+ T cells, one of the targets of immunotherapy treatment are epigenetically regulated. So, we utilized naïve and PD-1high CD8+ T cell ATAC-seq data to define the repertoire of accessible chromatin specific to these cell types. We found an enrichment of short cfDNA fragments at a significant fraction of these sites, enabling us to define responder-specific and non-responder-specific accessible PD-1high regions from cfDNA. Results: We used the enrichment of short- versus long-cfDNA fragments (reflecting transcription factor-nucleosome dynamics in tissue of origin of cfDNA) as a scoring function, and repeated-cross-validation as a classifier model to identify differentially enriched features between responders and non-responders. Our model accurately predicts the two classes of response both pre-treatment (mean test AUC = 0.86; SD = 0.14). Conclusions: Notably, in addition to generating an accurate classifier, our analysis enabled us to identify predominant transcription factor motifs from predictive ATAC-seq peaks that characterize both response and lack of response, paving the way for further understanding the mechanistic basis of patient-specific response to ICI. Our results suggest the possibility of personalized prediction of treatment response that is independent of specific tumor genotype.